Proc Amer Assoc Cancer Res, Volume 46, 2005
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Characterization of Chiral Tamoxifen Analogs Tamoxifen (TAM), a non-steroidal selective estrogen receptor modulator (SERM), is used for the treatment of estrogen receptor (ER) positive breast cancer. There are limitations however to its usefulness including a 4-fold increase of endometrial carcinoma associated with long term usage in postmenopausal women and the development of resistance. Based on these problems we have synthesized and evaluate a series of new chiral tamoxifen analogs. These stereo-selective chiral derivatives differ from TAM by replacement of the central double bond with a cyclopropyl moiety, introducing two chiral centers within the molecule. We hypothesize that novel chiral TAM analogs will demonstrate tissue specific activity through ER isotype (α and β) selectivity as well as inducing unique ligand-ER complex conformations. Our studies aim to direct the syntheses of future chiral TAM analogs by determining what effects altering the size, hydrophobicity and stereochemistry of a molecule have on its interaction with ER isotypes. Once characterized, these analogs are not only potential therapeutic agents, but become tools with which to assess SERM-ER interactions. Growth inhibitory properties were analyzed using MCF7-S (ER+ breast cancer cell line), its sublines TAM resistant MCF7/LCC2, Faslodex resistant MCF7/LCC9 (Brunner et al., Cancer Res. 57:3486, 1997) and the ER- breast cancer cell line BT-20. Cell growth was assessed using the sulforhodamine B colorimetric assay. Analog 99149 was found to be 3-fold more potent than TAM and 99148 (its enantiomer) using MCF7-S, while 02009 was found to be 2-fold more potent than TAM against resistant LCC2 cells. Isolated ER competitive binding data correlates ERα binding affinity with growth inhibitive activity in MCF7-S cells. Similar experiments performed with ERβ did not correlate with cell growth inhibitory activity. This suggests that ERα plays a vital role in SERM growth inhibitory activity in MCF7-S cells. Reporter plasmid XETL containing an estrogen response element (ERE) linked to a luciferase gene, enabled the evaluation of direct inhibition of ERE mediated gene expression. MCF7-S cells were transiently transfected with XETL and treated with 100nM of E2 and/or 2μM of TAM or analogs. Agent 99149 was found to be less potent than TAM in inhibiting ERE mediated transcription. This does not directly correlate with the growth inhibitory effects suggesting that the greater antiproliferative activity seen with 99149 may be due to drug effects other than inhibition of ERE gene expression. Structure-function relationships are being analyzed within a set of ten tamoxifen analogs. (This work is supported by NCI Student Training Grant CA09072-28)
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAdditions and Corrections - Some Short-Chain N6-Substituted Adenosine Analogues with Antitumor Properties.M. Fleysher, R. Bernacki, and G. BullardCite this: J. Med. Chem. 1981, 24, 12, 1540Publication Date (Print):December 1, 1981Publication History Published online15 September 2004Published inissue 1 December 1981https://pubs.acs.org/doi/10.1021/jm00144a602https://doi.org/10.1021/jm00144a602research-articleACS PublicationsRequest reuse permissionsArticle Views19Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
A murine melanoma variant (B16-F10ir6), resistant to lymphocytic cytolysis, has been shown previously to produce lower numbers of tumor nodules in the lung of C57BL/6J mice following i.v. inoculations. These differences found in tumor implantation and lymphocyte recognition may be due to changes in surface properties of this cell line. Therefore, membrane-bound sialic acid (released by Vibrio cholerae neuraminidase treatment), ectosialyltransferase activity, and total cellular glycosidase levels were measured in this cell line and compared with levels in its parent melanoma tumor cell line, B16-F10, which was selected for its enhanced ability to form tumor nodules. The results of these studies indicate a correlation between the degree of lung implantation and the amount of tumor cell sialic acid accessible to neuraminidase cleavage, tumor cell surface sialyltransferase activity, and several cellular glycosidase activities. These results are consistent with the idea that membrane structural changes in the glycocalyx may account for the ability of a tumor cell to implant and metastasize.
ABSTRACT L5178 Y murine leukemic cells do not seem to be affected by sucrose in the same manner as other mammalian cells. Although there is active uptake of sucrose with no concomitant metabolism, there is no increase in vacuolation or cell size and there is only a slight increase in acid phosphatase, acid protease and β-glucuronidase activities. However, the glycosidases are significantly elevated in the presence of 0·08 M sucrose. This may be due to a specific induction of these enzymes by the sucrose not related to a general increase in lysosomes. As the sucrose concentration is raised, a depression of the growth rate and an elevation of glycosidase activities occurs, reaching a maximum at 0·08 M sucrose. This depression of growth with a concomitant increase in generation time is primarily a result of the increased osmolarity of the medium; the same effect is observed with increased concentrations of NaCl. Although the growth effects are similar with either sucrose or NaCl, the elevation of glycosidase activity occurs only with increased concentrations of sucrose. Sucrose-induced vacuolation with an increase in cell size is not evident in L5178Y cells; therefore this effect does not seem to be common to all mammalian cells, even though it has been reported for LS cells, Chinese hamster fibroblasts, and chick bone rudiments and in vivo for liver cells.
